WO1995032212A1 - Procede de fabrication d'arabinonucleosides - Google Patents

Procede de fabrication d'arabinonucleosides Download PDF

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Publication number
WO1995032212A1
WO1995032212A1 PCT/EP1995/001343 EP9501343W WO9532212A1 WO 1995032212 A1 WO1995032212 A1 WO 1995032212A1 EP 9501343 W EP9501343 W EP 9501343W WO 9532212 A1 WO9532212 A1 WO 9532212A1
Authority
WO
WIPO (PCT)
Prior art keywords
general formula
esterase
arabino
nucleosides
producing
Prior art date
Application number
PCT/EP1995/001343
Other languages
German (de)
English (en)
Inventor
Heidi Hummel-Marquardt
Mario Kennecke
Alfred Weber
Thomas Schmitz
Ulf Tilstam
Klaus Nickisch
Original Assignee
Schering Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to CA002189130A priority Critical patent/CA2189130A1/fr
Priority to JP52999995A priority patent/JP4011107B2/ja
Priority to EP95916634A priority patent/EP0759926B1/fr
Priority to DE59503274T priority patent/DE59503274D1/de
Priority to US08/737,735 priority patent/US5712099A/en
Priority to DK95916634T priority patent/DK0759926T3/da
Publication of WO1995032212A1 publication Critical patent/WO1995032212A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/26—Preparation of nitrogen-containing carbohydrates
    • C12P19/28—N-glycosides
    • C12P19/38—Nucleosides
    • C12P19/40—Nucleosides having a condensed ring system containing a six-membered ring having two nitrogen atoms in the same ring, e.g. purine nucleosides

Definitions

  • the invention relates to a process for the preparation of arabinonucleosides of the general formula I.
  • X represents a hydrogen atom or a fluorine atom, from triacetates of the general
  • Lipase can act.
  • these compounds can be prepared from the triacetates of the general formula II by allowing them to act on this ethanolic ammonia solution (J.Org.Chem. 33. 1968. 432ff; Can .Cem. 59. 1981, 2608ff and Nucleic Acids Symp. Ser. 1981, 9, 61fr).
  • this process is not only quite complex, but also has the disadvantage that highly contaminated process products are obtained, in particular in the synthesis of fludarabine.
  • the process according to the invention can be carried out with relatively little effort and delivers the desired process products in high purity.
  • Lipases can be performed. Such are, for example
  • Protein (1U corresponds to the amount of enzyme which at 25 ° C and pH 8.0 l ⁇ mol
  • the substrate and enzyme are dissolved in a suitable buffer solution (citrate buffer, phosphate buffer, tris buffer, etc.) and shaken or stirred at 30 to 42 ° C. until complete conversion is achieved.
  • a suitable buffer solution citrate buffer, phosphate buffer, tris buffer, etc.
  • 1 to 10 g of substrate and 1 to 100 mg of enzyme are normally used per
  • Process product can be isolated in a simple manner by concentrating the reaction mixture. In order to be able to use the esterase several times, it is expedient to immolize it in a known manner (Tetrahedron 26 (no4) pp 407-410 (1985)). or to use a commercially available immobilized esterase (such as, for example, the one on Eupergit ® (immobilized esterase from pig liver from Fluka AG) to carry out the reaction).
  • immobilized esterase such as, for example, the one on Eupergit ® (immobilized esterase from pig liver from Fluka AG) to carry out the reaction.
  • the reaction solution obtained is practically free of 9 ⁇ -D-arabinofuranosyl-2-fluoro-9H-purine-6-amine monoacetate or diacetate. It is concentrated to a maximum of 5 ml at a bath temperature of 50 ° C., the precipitated product is filtered off with suction, washed with water and dried at 100 ° C. in vacuo. The 9 ⁇ -D-arabmofuranosyl-2-fluoro-9H-purine-6-aminine is thus obtained in quantitative yield.
  • Example 1 Under the conditions of Example 1, 0.500 g (2, 3,, 5'-tris-0-acetyl-D- 9SS-arabinofuranosyl) -2-fluoro-9H-purin-6-amine and 0.1 mg Schweineleber- Esterase (Sigma, Chem. St. Luis, USA 230 U / mg protein) reacted, processed and the 9 ⁇ -D-arabinoruranosyl-2-fluoro-9H-purine-6-amine is likewise obtained in quantitative yield.
  • Example 2 Under the conditions of Example 1, however, using 1.00 g (2 ', 3', 5'-tris-0-acetyl-9 ⁇ -D-arabinoruranosyl) -2-fluoro-9H-purine-6-amine 200 Incubated for hours.
  • the reaction solution is prepared as described in Example 1 and the 9 ⁇ -D-arabinofuranosyl-2-fluoro-9H-purine-6-amine is likewise obtained in quantitative yield.
  • pig liver esterase Boehringer Mannheim
  • the immobilizate is separated off and can then be reused up to 30 times.

Abstract

L'invention concerne un procédé de fabrication d'arabinonucléosides de formule générale (I), où X représente un atome d'hydrogène ou un atome de fluor, obtenus à partir de triacétates de formule générale (II), où X correspond à la signification mentionnée ci-dessus et les groupes Ac représentent chacun des groupes acétyle. Ce procédé est caractérisé en ce que l'on fait agir une estérase ou une lipase sur ces composés.
PCT/EP1995/001343 1994-05-20 1995-04-13 Procede de fabrication d'arabinonucleosides WO1995032212A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA002189130A CA2189130A1 (fr) 1994-05-20 1995-04-13 Procede de fabrication d'arabinonucleosides
JP52999995A JP4011107B2 (ja) 1994-05-20 1995-04-13 アラビノヌクレオシドの製法
EP95916634A EP0759926B1 (fr) 1994-05-20 1995-04-13 Procede de fabrication d'arabinonucleosides
DE59503274T DE59503274D1 (de) 1994-05-20 1995-04-13 Verfahren zur herstellung von arabinonukleosiden
US08/737,735 US5712099A (en) 1994-05-20 1995-04-13 Process for the production of arabinonucleosides
DK95916634T DK0759926T3 (da) 1994-05-20 1995-04-13 Fremgangsmåde til fremstilling af arabinonucleosider

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4418474.3 1994-05-20
DE4418474A DE4418474A1 (de) 1994-05-20 1994-05-20 Verfahren zur Herstellung von Arabinonucleosiden

Publications (1)

Publication Number Publication Date
WO1995032212A1 true WO1995032212A1 (fr) 1995-11-30

Family

ID=6519072

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/001343 WO1995032212A1 (fr) 1994-05-20 1995-04-13 Procede de fabrication d'arabinonucleosides

Country Status (9)

Country Link
US (1) US5712099A (fr)
EP (1) EP0759926B1 (fr)
JP (1) JP4011107B2 (fr)
AT (1) ATE169928T1 (fr)
CA (1) CA2189130A1 (fr)
DE (2) DE4418474A1 (fr)
DK (1) DK0759926T3 (fr)
ES (1) ES2123246T3 (fr)
WO (1) WO1995032212A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20020052A1 (it) * 2002-01-14 2003-07-14 Innovate Biotechnology Srl Procedimento per l'idrolisi selettiva di nucleosidi poliesteri
CN102911230A (zh) * 2012-04-16 2013-02-06 淮海工学院 一种氟达拉滨的合成方法
JP7381913B2 (ja) * 2021-10-13 2023-11-16 ダイキン工業株式会社 有害生物防除組成物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1159290A (en) * 1966-12-30 1969-07-23 Parke Davis & Co Fermentation process for 9-(beta-D-Arabinofuranosyl) Adenine
US4055718A (en) * 1976-05-17 1977-10-25 Parke, Davis & Company 9-(2-O-Acyl-β-D-arabinofuranosyl)-adenine compounds and method for their production
US4212941A (en) * 1977-05-23 1980-07-15 Warner-Lambert Company Method for the production of 9-(2-O-acyl-β-D-arabinofuranosyl)adenine compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1159290A (en) * 1966-12-30 1969-07-23 Parke Davis & Co Fermentation process for 9-(beta-D-Arabinofuranosyl) Adenine
US4055718A (en) * 1976-05-17 1977-10-25 Parke, Davis & Company 9-(2-O-Acyl-β-D-arabinofuranosyl)-adenine compounds and method for their production
US4212941A (en) * 1977-05-23 1980-07-15 Warner-Lambert Company Method for the production of 9-(2-O-acyl-β-D-arabinofuranosyl)adenine compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MONTGOMERY J.A. AND HEWSON K.: "A Convenient Method for the Synthesis of 2-Fluoroadenosine", JOURNAL OF ORGANIC CHEMISTRY, vol. 33, no. 1, EASTON US, pages 432 - 434 *

Also Published As

Publication number Publication date
DK0759926T3 (da) 1999-05-25
EP0759926B1 (fr) 1998-08-19
DE59503274D1 (de) 1998-09-24
US5712099A (en) 1998-01-27
ATE169928T1 (de) 1998-09-15
ES2123246T3 (es) 1999-01-01
JPH10507063A (ja) 1998-07-14
CA2189130A1 (fr) 1995-11-30
DE4418474A1 (de) 1995-11-23
JP4011107B2 (ja) 2007-11-21
EP0759926A1 (fr) 1997-03-05

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